This is a revised application to establish a multi-institutional CLL Research Consortium (CRC) that will research the biologic basis of CLL and investigate novel biologic and pharmacologic treatments for this disease. The CRC ill establish a multi-institutional CLL Clinical Consortium to enable uniform, high-volume sample accrual and inter- institutional phase I/II clinical studies. This will allow the CRC to research novel treatments for CLL, and to examine for clinical <-> laboratory relationships that ultimately may permit improved clinical staging and/or assist in the evaluation of the response of novel therapies.. Furthermore, the CRC will develop and maintain an interactive Website for CRC investigators (see: http://orpheus.ucsd.edu/hemonc/crc/index.html), a sophisticated national tissue bank, and a secured on-line relational database that will permit basic and clinical research studies on disease heterogeneity among patients with CLL, or in any one CLL patient over time. Finally, the CRC will develop a Clinical Advisory Committee that can advice established cooperative groups on the relative merits of novel treatment strategies being considered for phase III testing. The grant has six major projects. Project 1 (Croce PI) investigates the genetic basis for CLL. Project 2 (Reed PI) investigates the leukemia-cell expression of genes and proteins important in the regulation of apoptosis and in defining the leukemia cells' resistance to pharmacologic antigens and novel techniques for active therapy. Project 3 (Kipps PI) examines for leukemia-associated antigens and novel techniques for active therapy. Project 3 (Kipps PI) examines for leukemia-associated antigens and novel techniques for active immunotherapy of this disease, including gene therapy. Project 4 (Gribben PI) examines T cell anergy, stem cell transplantation, and the potential for adoptive immunotherapy of CLL using autologous or allogeneic leukemia-transplantation, and the potential for adoptive immunotherapy of CLL using autologous or allogeneic leukemia-specific T cells. Project 5 (Plunkett PI) examines some of the most promising lead compounds for phase I/II testing CLL and examines the mechanisms of action of these agents acting alone or in mechanism-based combinations. Project 6 (Keating PI) examines some of the most promising lead compounds for phase I/II testing CLL and examines the mechanisms of action of these agents alone or in mechanism-based combinations CLL and examines the mechanisms of action of these agents acting alone or in mechanism-based combination parameters that may serve as prognostic indicators in CLL. In addition. this project establishes the CLL Clinical Consortium (CCC). The CRC has 3 cores: Core A (Kipps PI) is the administrative core that will coordinate research investigations, oversee the generation and maintenance of the clinical and laboratory databases, maintain the CRC Website and listserver, organize meetings and teleconferences between members of the project and outside reviewers, and provide for research data nurse support at CRC clinical sites. Core B is the Biostatistics Core (Neuberg PI) that will assist investigators in the biostatistical design and implementation of basic and clinical research projects. ore C (Rassenti PI) is the Tissue Core. This core is responsible for tissue banking, sample trafficking, and leukemia sample laboratory testing and sample-validation. Through this CRC we will expedite research aimed at achieving better understanding of the biologic basis of this disease and its eventual cure.